1. Field of the Invention
This invention relates to tripeptide and tetrapeptide thioethers, pharmaceutical compositions containing them, their pharmaceutical use, and their preparation.
2. Description of the Related Art
U.S. Pat. Nos. 5,599,903; 5,763,570; 5767086; 5786336; and 5955432; European Patent Publication No. 0 645 397; and PCT International Publications Nos. WO 95/08563 and WO 96/40205 disclose various tripeptide and tetrapeptide compounds that are analogs of reduced glutathione (L-γ-glutamyl-L-cysteinylglycine), including compounds of the formula [WO 95/08563]:
and their C1-10 alkyl or alkenyl or C7-12 aralkyl esters, amides, and mixed ester/amides, where:Z is S, O, or C;n is 1 to 3;when Z is S or O and n is 1, X is a C1-20 hydrocarbyl optionally containing 1 or 2 non-adjacent O, S, or N heteroatoms, unsubstituted or mono- or disubstituted with halo, —NO, —NO2, —NR2, —OR, or —SR, where R is H or C1-4 alkyl;when Z is S and n is 2, one X is as above defined and the other X is C1-4 alkyl; andwhen Z is C and n is 3, one X is as above defined and the other two X are independently H or C1-4 alkyl;YCO is γ-glu, β-asp, glu, asp, γ-glu-gly, β-asp-gly, glu-gly, asp-gly; andAAc is an amino acid coupled through a peptide bond to the remainder of the compound.
The compounds are described as having various uses, including as reagents useful in characterizing glutathione S-transferase (GST) isoenzymes, in determining the GST complements of cells and tissues, as chromatographic affinity ligands, binding agents, and enzyme inhibitors; and therapeutically to: potentiate the cytotoxic effects of chemotherapeutic agents in tumor cells, selectively exert cytotoxicity in tumor cells, elevate the production of granulocyte-mactophage (GM) progenitors in bone marrow, stimulate the differentiation of bone marrow cells, mitigate the bone marrow-destructive effects of chemotherapeutic agents, and modulate hematopoiesis in bone marrow.
TLK117, identified in those patents and publications as TER 117 and named variously as γ-Glu-Cys(Bz)-phenylGly, γE-C(Bz)-φG, γE-C(Bz)-PG, γE-C(benzyl)-φG, and benzyl PG, is one of these compounds. TLK117 is the compound of the formula
and may be named L-γ-glutamyl-S-(phenylmethyl)-L-cysteinyl-D-phenylglycine. TLK117 inhibits GST P1-1 with an IC50 of approximately 400 nM. TLK199, identified in those patents and publications as TER 199, is the diethyl ester of TLK117.
U.S. Pat. No. 6,627,732 and PCT International Publication No. WO 99/54346 disclose glutathione derivatives of the formula
whereA is H or C1-20 acyl;R1 is C1-26 alkyl or C3-26 alkenyl; andR2 is H, C1-26 alkyl, or C3-26 alkenyl;excluding the case where R1 is C1-10 alkyl or C3-10 alkenyl and R2 is H, C1-10 alkyl or C3-10 alkenyl.
US Published Application No. 2003/0100511 and PCT International Publication No. WO 00/44366 disclose lipid formulations, including liposomal formulations, of diesters of compounds of the formula:
where:each ester is 1–25C;YCO is γ-glu or β-asp;G* is phenylglycine;Z is CH2, O, or S; andX is 6–8C alkyl, benzyl, or naphthyl,or a pharmaceutically acceptable salt thereof; ora compound of the formula:
where:R1 and R2 are independently chosen from linear or branched alkyl groups (1–25C), cycloalkyl groups (6–25C), substituted alkyl groups (2–25C), heterocycles (6–20C), ethers or polyethers (3–25C), or where R1–R2 (2–20C) together form a macrocycle with the formula; andR3 is 6–8C alkyl, benzyl, or naphthyl,or a pharmaceutically acceptable salt thereof.
Many conditions are characterized by depleted bone marrow, including myelodysplastic syndrome (MDS), a form of pre-leukemia in which the bone marrow produces insufficient levels of one or more of the three major blood elements (white blood cells, red blood cells and platelets). A reduction in blood cell levels and the generation of new blood cells in the bone marrow, myelosuppression, is also a common, toxic effect of many standard chemotherapeutic drugs.
TLK199 has been shown to induce the differentiation of HL-60 promyelocytic leukemia cells in vitro, to potentiate the activity of cytotoxic agents both in vitro and in vivo, and to stimulate colony formation of all three lineages of hematopoietic progenitor cells in normal human peripheral blood. In preclinical testing, TLK199 has been shown to increase white blood cell production in normal animals as well as in animals in which white blood cells were depleted by treatment with cisplatin or fluorouracil. Similar effects may provide a new approach to treating MDS. TLK199 is currently being evaluated in a Phase II clinical trial for the treatment of MDS. Interim results from this trial, reported at the 2004 and 2005 American Society of Hematology meetings, demonstrated that TLK199 was well tolerated and resulted in multilineage hematologic improvement. These results also suggest a potential role for TLK199 in treating chemotherapy-induced cytopenias.
It would be desirable to develop potent inhibitors of GST P1-1 for use in humans to: potentiate the cytotoxic effects of chemotherapeutic agents in tumor cells, selectively exert cytotoxicity in tumor cells, elevate the production of GM progenitors in bone marrow, stimulate the differentiation of bone marrow, mitigate the myelosuppressive effects of chemotherapeutic agents, and modulate hematopoiesis in bone marrow.